Cefepime in intensive care unit patients: validation of a population pharmacokinetic approach and influence of covariables.

AIM: The purpose of our study was to define and validate a population-pharmacokinetic model including the influence of patients' characteristics on the pharmacokinetics of cefepime. PATIENTS AND METHODS: A total of 55 patients were randomized in Group 1 (34 patients, 320 cefepime concentrations) for the model building and Group 2 (21 patients, 196 cefepime concentrations) for the validation group. They received cefepime as 2 g A 2 or as 4 g continuously. The population pharmacokinetic analysis was carried out using NONMEM and a baseline model was constructed for studying the influence of demographic and biological variables. The model was then validated by a comparison of the predicted and observed concentrations in Group 2. A final model was elaborated from the whole population. RESULTS: Total clearance (CL) was significantly correlated with the serum creatinine (CREA) and the central volume of distribution (V1) was correlated with the body weight (WT). The final model was: CL = 7.14 + (-0.0133 A CREA). V1 = (-16.8) + (0.475 A WT). Q (intercompartmental clearance) = 10.5. V2 = 18.1. The mean pharmacokinetic parameters and their individual variability were: CL (8.24 l/h, 45%), V1 (20.89 l, 60%), V2 (17.95 l, 49%), total volume (38.85 l, 42%) and Q (10.56 l/h, 9%). The bias (1.07 mg/l, IC 95% = -40.46 -+42.60), precision (21.19%) and AFE (1.15) demonstrated the performance of the model. CONCLUSION: We have developed and validated a pharmacokinetic model to estimate cefepime concentrations. We showed that serum creatinine and body weight are factors that may influence the standard dose of cefepime. Our model enabled us to predict cefepime concentrations in other patients.

Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen.

The aim of this study was to compare the pharmacokinetic and pharmacodynamic parameters of a continuous infusion of cefepime vs. an intermittent regimen in critically ill adult patients with Gram-negative bacilli infection. The prospective randomized parallel study was carried out in 50 patients with severe pneumonia (n = 41) or bacteremia (n = 9). They received cefepime 4 g/d either as a continuous infusion or intermittent administration 2 x 2 g in combination with amikacin. Patient characteristics and the minimal inhibitory concentration (MIC) of the isolated bacteria were comparable. Clinical outcomes were assessed along with pharmacodynamic indices and compared in both groups (chi2 and Mann-Whitney U-tests). Mechanical ventilation, clinical outcome and bacteriological eradication did not significantly differ between the two groups. Also, the area under the plasma cefepime concentration curve at steady state (AUCss: 612 +/- 369 vs. 623 +/- 319 mg x 1(-1) x h), AUCss > MIC (595 +/- 364 vs. 606 +/- 316 mg x 1(-1) x h) and the area under the inhibitory concentration curve (AUICss: 4258 +/- 5819 vs. 5194 +/- 7465 mg x 1(-1) x h) were similar. If the time above MIC (t > MIC) was not significantly higher in Group 1 (100 +/- 0%) than in Group 2 (90 +/- 11%), t > five-fold MIC in Group 1 (100 +/- 0%) was significantly higher (p < 0.01) than in Group 2 (82 +/- 25%). The mean time over the French breakpoint (4 mg/l) was 100 +/- 0% and 72 +/- 27% in Group 1 and 2 (p < 0.001), respectively. In contrast to intermittent cefepime administration, continuous infusion of cefepime consistently maintained a serum concentration > 5 x the MIC of typical Gram-negative nosocomial pathogens. This results in greater bactericidal activity against organisms with a higher (2 mg/l) cefepime breakpoint even if the clinical outcome is not significantly modified.

[Importance of a cefpirome-vancomycin combination on bactericidal kinetics in severe MRSA infections in intensive care]. / Intérêt de l'association cefpirome-vancomycine sur la cinétique de bactéricidie dans les infections sévères à SAMR en réanimation.

UNLABELLED: Vancomycin is always the drug of choice for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in spite of his bactericidal kinetic. BACKGROUND: The aim of this study was to evaluate in vivo the improvement of bactericidal kinetic of vancomycin associated with cefpirome against MRSA infection in critically ill patients. METHODS: The prospective cross-over study was carried out in 20 patients with severe pneumonia or bacteremia. There were randomized to receive vancomycin 2 g per day (Group 1, n = 10) or vancomycin with cefpirome 2 g x 2 (Group 2, n = 10). Clinical recovery, bacteriologic parameters (bactericidal kinetic and bactericidal power in vivo at the peak and the valley), duration of ventilation and stay in ICU were comparatively explored in both groups. RESULTS: Clinical outcome did not significantly differ between Group 1 and 2. Bactericidal kinetics were better in the Group 2 (40% vs 60% after 6 hours to the dilution for 1/8e) but the difference was not significant. However, bactericidal power in sera was also better in the Group 2 with more bactericidal dilution at 1/16e (68% vs 88.8%: NS) and overall at 1/32e (10.5% vs 50%: p < 0.05) and CRP, an inflammatory marker, was significantly lower in the Group 2 than in the Group 1 (119.5 +/- 24 mg/l vs 198.6 +/- 78 mg/l: p < 0.05) on the third day.

[Management of acute respiratory distress syndrome in Midi-Pyrnees]. / Prise en charge du syndrome de détresse respiratoire aiguë en Midi-Pyrénées.

OBJECTIVE: To assess management of acute respiratory distress syndrome (ARDS) in Midi-Pyrénées, France. METHODS: A prospective study using a questionnaire divided into 10 parts, definition, etiology, radiography, computed tomography, management, was conducted in 26 intensive care units in the Midi-Pyrénées. Management of ARDS in Midi-Pyrénées was comparted with management elsewhere as described in the literature. RESULTS: Overall participation rate was 73%. Disparities were found concerning the definition. Four etiologies accounted for 75% of all ARDS cases. Chest x-rays were used for positive diagnosis and thoracic scans for complications. Ventilatory and hemodynamic optimizations were the first line therapy used. Twenty-nine percent and 41% of the intensive care unites used nitric oxide and prone position respectively. CONCLUSIONS: There are differences between ARDS management in Midi-Pyrénées and that described in the current literature. Epidemiologic studies such as this one are necessary before publishing guidelines for the management of ARDS.

[Duration of antibiotic treatment in intensive care: current data]. / Durée du traitement antibiotique en réanimation: données actuelles.

OBJECTIVE: To review the current data on the duration of an antibiotic treatment. METHODS: Analysis of recent and older articles on criteria of discontinuation of an antibiotic treatment in intensive care patients. SYNTHESIS: In intensive care patients the initiation of an antibiotic therapy is more or less codified, in spite of numerous existing problems. The duration of its maintenance, although based on scientific data depends mainly on a multitude of variables. The first step is to assess the therapeutic efficiency in considering the regression of clinical manifestations, the normalization of the acute phase reactants, the sterility of bacteriological samples and the absence of relapse at therapy discontinuation. An assessment after 48 hours is essential, in order to decide the maintenance or the modification of therapy. Finally the indication of bitherapy is considered. The theoretical duration of antibiotic therapy is determined in taking into account the involved microbial agent(s), the centre of infection, the bacterial inoculum, the patient, the presence of foreign material, and the administered antibiotic.

[Continuous versus intermittent cefepime infusion in critical care. Preliminary results]. / Perfusion continue versus administration discontinue de céfépime en réanimation. Résultats préliminaires.

The bactericidal activity of beta-lactams is time-dependent, and the time spent above the MIC (T > MIC) is the best predictor of efficacy. A prospective, randomized, open-label study was conducted in intensive care unit (ICU) patients with gram-negative rod infections to compare the efficacy of cefepime given as a continuous versus an intermittent infusion. Of the 18 patients included to date, 14 had severe pneumonia and four bacteremia. All patients received amikacin, 15 mg/kg/d, and cefepime, 4 g/d. Patients were randomized to cefepime administration as a continuous infusion (Group 1, n = 9) or as an intermittent infusion (Group 2, n = 9, 2 g every 12 h). No significant differences were found between the two groups for age, sex, initial infection, IGS II score (46 vs 48, NS) or the MIC of the gram-negative organism. Mechanical ventilation and hospital stay durations, recovery rates, and pharmacokinetic parameters (24-h AUIC, 12-h AUIC, T > MIC, and T > 5 x MIC) were compared in the two groups using the chi-square and Mann-Whitney tests. P values < 0.05 were considered statistically significant. There were no significant differences for mechanical ventilation duration, recovery rate, hospital stay duration (34 vs 36 days, NS), 24-h AUIC (624 vs 473, NS), or the 12-h AUIC (235 vs 238, NS). There were two interesting findings: T > MIC was significantly (P < 0.05) higher in Group 1 (23.84 +/- 0.2) than in Group 2 (20.7 +/- 3), and T > 5 x MIC was also significantly (P < 0.01) higher in Group 1 (23.61 +/- 0.6) than in Group 2 (16.6 +/- 6). Although clinical outcomes were similar in the two groups, it is reasonable to assume that the longer time spent with a cefepime level above the MIC in the continuous infusion group was associated with a more stable bactericidal effect.

[Severe methicillin-resistant Staphylococcus aureus infections. Emergence of resistance to fusidic acid or fosfomycin during treatment with continuous infusion of vancomycin]. / Infections sévères à Staphylococcus aureus mticillino-résistants. Emergence de résistance à l'acide fusidique ou à la fostomycine lors du traitement par vancomycine en perfusion continue.

OBJECTIVES: To evaluate the development of resistance to fosfomycin or fucidic acid in severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and to assess the relationship with serum levels of vancomycin METHODS: A retrospective study was performed in patients hospitalized in our intensive care unit during a 3-year period (1993-1995) who were treated for severe MRSA infection with continuous infusion vacomycin and fosfomycin or fucidic acid. We analyzed the development of resistance and serum levels of vancomycin. RESULTS: During this period, only 20 patients received continuous infusion vancomycin plus fucidic acid or fosfomycin. MSRA resistant to fucidic or fosfomycin developed in 9. Vancomycin serum levels were significantly lower in patients who developed resistance to focidic acid or fosfomycin, both during the first 5 days of treatment (16.68 +/- 1.07 micrograms/ml vs. 22.64 +/- 1.05 mg/ml, p < 0.01) and throughout treatment duration (17.29 +/- 1.07 micrograms/ml vs. 21.85 +/- 0.78 microgram/ml, p < 0.01). CONCLUSIONS: Our findings confirm that in spite of continuous vancomycin infusion at an initial rate of 2 g/24 h, Staphylococcus aureus resistance to fosfomycin or fucidic acid an develop during ongoing treatment. Vancomycin levels of at least 20 micrograms/ml should be obtained as rapidly as possible.

[Evaluation of 2 bacterial filters connected to the respirator for the prevention of nosocomial pulmonary infection]. / Evaluation de deux filtres de rétention bactérienne branchés sur respirateur dans la prévention de l'infection pulmonaire nosocomiale.

Among 37 patients that are admitted for a more than 3 days breathing reanimation, 19 are ventilated with bacterial filter Pall BB 22 15 and 18 with Darex Hygrobac, exchanged every days and connected to the Y piece. In this study, 6 patients are ventilated with a humidifier (pilot population). For these 43 patients, 130 protected swabs were made with the RCS Biotest placed on the expired gaz. The day of the taking off the expiratory tube was rinsed with 100 ml of aseptic water which are strained on the membrane. The two filters give very good and comparable bacteriological results. The filters prevents nosocomial pulmonary infections making a bacterial frontier between the patient and the respirator and reducing aerial contamination from one patient to another.